OBJECTIVE: To determine whether daily administration of pyrantel tartrate can prevent infection in horses experimentally challenged with Sarcocystis neurona. ANIMALS: 24 mixed-breed specific-pathogen-free weanling horses, 10 adult horses, 1 opossum, and 6 mice. PROCEDURE: Sarcocystis neurona-naïve weanling horses were randomly allocated to 2 groups. Group A received pyrantel tartrate at the labeled dose, and group B received a nonmedicated pellet. Both groups were orally inoculated with 100 sporocysts/d for 28 days, 500 sporocysts/d for 28 days, and 1000 sporocysts/d for 56 days. Blood samples were collected weekly, and CSF was collected monthly. Ten seronegative adult horses were monitored as untreated, uninfected control animals. All serum and CSF samples were tested by use of western blot tests to detect antibodies against S. neurona. At the end of the study, the number of seropositive and CSF-positive horses in groups A and B were compared by use of the Fisher exact test. Time to seroconversion on the basis of treatment groups and sex of horses was compared in 2 univariable Cox proportional hazards models. RESULTS: After 134 days of sporocyst inoculation, no significant differences were found between groups A and B for results of western blot tests of serum or CSF There were no significant differences in number of days to seroconversion on the basis of treatment groups or sex of horses. The control horses remained seronegative. CONCLUSIONS AND CLINICAL RELEVANCE: Daily administration of pyrantel tartrate at the current labeled dose does not prevent S. neurona infection in horses.